Alpha- haloenamine reagents

ABSTRACT

The present invention describes immobilized haloenamine reagents, immobilized tertiary amides, methods for their preparation, and methods of use.

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/316,151, filed on Aug. 30, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention relates in general to the field ofα-haloenamine chemistry, processes for the preparation of α-haloenaminesand, in one embodiment, to α-haloenamine reagents supported by anorganic or inorganic material which, under a defined set of conditions,renders the supported reagent sufficiently insoluble to enableseparation of the reagent from a mixture.

[0003] α-Haloenamine reagents are used in a number of syntheticreactions. For example, they are used to convert carboxylic acids toacid halides, alcohols to halides, sugars to sugar halides, andthiophosphoryl compounds to the corresponding phosphoryl halides.α-haloenamine reagents offer advantages over other reagents for suchconversions, particularly under neutral conditions and in thoseinstances in which the substrate for the reaction contains one or moresensitive functionalities.

[0004] Despite these advantages, haloenamines are not being used totheir full potential for a variety of reasons. Among these reasons aresynthetic challenges. Ghosez et al. (Angew. Chem. Int. Ed. Engl. 1969,8, 454) disclosed a route which involved the reaction of tertiary amideswith phosgene followed by the dehydrochlorination of the intermediateα-chloroiminium salts with triethylamine. According to Ghosez et al.,the hazard associated with the use of large amounts of phosgene as wellas the ban on phosgene in many laboratories led them to re-examine thepreparation of β-disubstituted-α-chloroenamines; more recently, Ghosezet al. (Tetrahedron 54 (1998) 9207-9222) reported a synthetic routewhich was said to be conceptually the same as the previous one: itinvolved the reaction of a tertiary amide with a chlorinating agentfollowed by the elimination of hydrochloric acid from the resultingα-chloroiminium salt. The halogenating agents tried by Ghosez et al.were thionyl chloride, diphosgene, triphosgene, phosphorous oxychloride,and phosphorous oxybromide. Of these, only phosphorous oxychloride wassaid to be suitable for the preparation of large amounts ofα-chloroenamines. Thionyl chloride was said to be unsuitable. Diphosgeneand triphosgene were said to be suitable although in both cases a minorby-product was produced. As a result, Ghosez et al. stated thatphosphorous oxychloride would probably supersede phosgene as thehalogenating agent. Ghosez et al. also reported that they succeeded inpreparing the corresponding α-bromoenamines which, until then, they saidwere only available by halide exchange. Despite the advances reported byGhosez et al., the conversion of a tertiary amide to an α-chloroiminiumsalt, particularly when the nitrogen substituents are bulky can bedifficult.

[0005] Recent advances in molecular biology, chemistry and automationhave resulted in the development of rapid, high throughput screening(HTS) protocols to synthesize and screen large numbers of compounds fora desired activity or other desirable property in parallel. Theseadvances have been facilitated by fundamental developments in chemistry,including the development of highly sensitive analytical methods, solidstate chemical synthesis, and sensitive and specific biological assaysystems. As a result, it is now common to carry out such reactions, inparallel, in a multi-well micro titer plate or other substratum having aplurality of wells for containing a reaction mixture, e.g., 96, 384 oreven a greater number of wells. To date, however, α-haloenamine reagentshave not been provided in a form which would enable rapid, automated useand purification from such reaction mixtures.

SUMMARY OF THE INVENTION

[0006] One aspect of the present invention, therefore, is an improvedprocess for the preparation of α-haloenamines. The resultingα-haloenamines may be used in a wide variety of synthetic schemes, suchas the conversion of hydroxy-containing compounds and thiol-containingcompounds to the corresponding halides. If immobilized onto a support,the resulting α-haloenamines are particularly useful in high-throughput,automated and other systems where ease of separation is desired.

[0007] Briefly, therefore, the present invention is directed to animmobilized haloenamine reagent having the formula:

[0008] wherein

[0009] R₁ and R₄ are independently hydrocarbyl, substituted hydrocarbyl,hydrocarbyloxy, or substituted hydrocarbyloxy;

[0010] R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio,hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl,hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl,thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro, and

[0011] X is halo,

[0012] provided at least one of R₁, R₂, R₃ and R₄ comprises a supportwhich enables physical separation of the reagent from a liquid mixture.

[0013] The present invention is further directed to a process for thepreparation of an α-haloenamine. The process comprises combining atertiary amide with a pentavalent phosphorous halide in a solvent toform an α-haloiminium salt and converting the α-haloiminium salt to theα-haloenamine with a base, the pentavalent phosphorous halide having atleast two halogen atoms bonded to the pentavalent phosphorous atom.

[0014] The present invention is further directed to a process fordehydrating a non-aqueous solvent. The process comprises combining thesolvent with an immobilized α-haloenamine reagent.

[0015] The present invention is further directed to a process forconverting a hydroxy-containing compound or a thiol-containing compoundto the corresponding halide. The process comprises contacting thehydroxy-containing compound or thiol-containing compound with animmobilized α-haloenamine. The hydroxy-containing compound may beselected, for example, from the group consisting of alcohols, carboxylicacids, silanols, sulfonic acids, sulfinic acids, phosphinic acids,phosphoric acids, and phosphates.

[0016] The present invention is further directed to an immobilizedtertiary amide reagent having the formula:

[0017] wherein

[0018] R₁ and R₄ are independently hydrocarbyl, substituted hydrocarbyl,hydrocarbyloxy, or substituted hydrocarbyloxy; and

[0019] R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio,hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl,hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl,thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro,

[0020] provided at least one of R₁, R₂, R₃ and R₄ comprises a supportwhich enables physical separation of the reagent from a liquid mixture.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] A. Preparation of α-Haloenamines

[0022] In accordance with one aspect of the present invention,α-haloenamines may be prepared from tertiary amides and pentavalentphosphorous halides. The tertiary amide reacts with the pentavalentphosphorous halide to produce a haloiminium salt which is then convertedto the α-haloenamine with a base.

[0023] In general, the tertiary amide may be any tertiary amide having ahydrogen atom bonded to the carbon which is in the alpha positionrelative to the carbonyl group of the tertiary amide and which does notinterfere with the synthesis of or react with the α-haloenamine. In oneembodiment, the tertiary amide has the general formula:

[0024] wherein

[0025] R₁ and R₄ are independently hydrocarbyl, substituted hydrocarbyl,hydrocarbyloxy, or substituted hydrocarbyloxy; and

[0026] R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio,hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl,hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl,thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro.

[0027] Ordinarily, it will be preferred that R₂ and R₃ are other thanhydrogen, such as alkyl or aryl to increase the stability of the reagentto a variety of conditions. Nevertheless, under some circumstances,provided one of R₂ and R₃ is sufficiently electron-withdrawing, theother may be hydrogen. Under other circumstances, each of R₂ and R₃ iselectron withdrawing. In no event, however, may R₂ and R₃ each behydrogen.

[0028] In one embodiment of the present invention, one of R₁, R₂, R₃ andR₄ comprises a support which enables physical separation of the tertiaryamide (or a derivative thereof) from a liquid mixture. The support maybe, for example, any solid or soluble, organic or inorganic supportwhich is conventionally used in chemical synthesis or any of a varietyof assays. Such supports are described in greater detail elsewhereherein in connection with the supported α-haloenamine reagents of thepresent invention. Preferably, it is polystyrene or a derivativethereof, for example, a 1% cross linked polystyrene/divinyl benzenecopolymer.

[0029] The pentavalent phosphorous halide comprises at least two halogenatoms bonded to a pentavalent phosphorous atom. The three remainingvalences are optionally occupied by bonds to carbon or halogen atoms. Ingeneral, therefore, the pentavalent phosphorous halide may berepresented by the general formula P(X)₂(Z)₃ wherein each X isindependently a halogen atom and each Z is independently a halogen atomor a carbon atom (which is part of a hydrocarbyl or substitutedhydrocarbyl radical). For example, included within this general formulaare pentavalent phosphorous halides in which the pentavalent phosphorousatom is bonded to two, three, four, or five halogen atoms selected fromamong chlorine, bromine and iodine. If fewer than five halogen atoms arebonded to the pentavalent phosphorous atom, the remaining valences areoccupied by phosphorous-carbon bonds with the carbon being part of ahydrocarbyl or substituted hydrocarbyl radical, preferably phenyl orlower alkyl (e.g., methyl, ethyl or isopropyl). Although mixed halidesare theoretically possible and within the scope of the presentinvention, for most applications it will generally be preferred thathalogen atoms of only one type (e.g., only chlorine, bromine or iodine)be attached to the pentavalent phosphorous atom. Phosphorouspentachloride and phosphorous pentabromide are particularly preferred.

[0030] The α-haloiminium salt resulting from the reaction of thetertiary amide and the pentavalent phosphorous compound may be convertedto the α-haloenamine with an amine base such as N,N-dialkyl anilines,trialkylamines, heterocyclic amines, pyridines, N-alkylimidazole, DBUand DBN. Tertiary amine bases such as triethylamine are generallypreferred; other amine bases, however, such as substituted pyridines maybe preferred under certain circumstances.

[0031] In general, therefore, and in accordance with one aspect of thepresent invention, α-haloenamines of the present invention may beprepared in accordance with the following reaction scheme:

[0032] wherein

[0033] R₁ and R₄ are independently hydrocarbyl, substituted hydrocarbyl,hydrocarbyloxy, or substituted hydrocarbyloxy;

[0034] R₂ and R₃ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio,hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl,hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl,thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro, and

[0035] each X is independently chlorine, bromine or iodine; and

[0036] each Z is independently chlorine, bromine, iodine, hydrocarbyl orsubstituted hydrocarbyl.

[0037] The reaction may be carried out in acetonitrile, another solvent,or a mixture of solvents in which pentavalent phosphorous and thetertiary amide are sufficiently soluble. Other solvents include etherealsolvents (e.g., tetrahydrofuran, and 1,4-dioxane), esters (e.g., ethylacetate), halogenated solvents (e.g., methylene chloride, chloroform and1,2-dichloroethane), and under certain conditions, hydrocarbon solvents(e.g., toluene and benzene). If the solvent system comprises a mixtureof solvents, the solvent system preferably comprises at least about 10%by weight, more preferably at least about 20% by weight acetonitrile.

[0038] If desired, the halogen atom, X, of the resulting α-haloenamine(e.g., the chlorine atom of α-chloroenamine or the bromine atom ofα-bromoenamine) may be displaced by another halogen atom to form otherα-haloenamine derivatives. Thus, for example, the chlorine atom of anα-chloroenamine may be displaced by a bromide, fluoride or iodide atom.Similarly, the bromine atom of an α-bromoenamine may be displaced by afluoride or iodide atom. In general, the displacement may be carried outwith an alkali metal halide (e.g., sodium, potassium, cesium or lithiumbromide, fluoride or iodide).

[0039] B. Immobilized α-Haloenamine Reagents

[0040] The immobilized α-haloenamine reagent of the present inventioncomprises an α-haloenamine component tethered to a support which enablesphysical separation of the reagent from a liquid composition. Theα-haloenamine component is tethered to the support by means of a linkerand, optionally, a spacer. The immobilized α-haloenamine reagents of thepresent invention generally correspond to the formula

[0041] wherein X is halogen, and R₁, R₂, R₃ and R₄ are as previouslydefined provided, however, at least one of R₁, R₂, R₃ and R₄ comprises asupport which enables physical separation of the reagent from a liquidcomposition. In general, reactivity tends to be greater when R₁, R₂, R₃and R₄ are less bulky and when R₁, R₂, R₃ and R₄ are alkyl or aryl.Preferably, therefore, R₁, R₂, R₃ and R₄ are independently hydrocarbylor substituted hydrocarbyl, more preferably hydrocarbyl, still morepreferably alkyl or aryl, provided at least one of R₁, R₂, R₃ and R₄comprises a support which enables physical separation of the reagentfrom a liquid composition.

[0042] In one embodiment, the α-haloenamine reagent support is a solidwhich is insoluble under all pertinent conditions. In anotherembodiment, the haloenamine reagent support is a composition which isselectively soluble in a solvent system; under a first set ofconditions, the support is soluble but under a second set of conditions,the support is insoluble.

[0043] Insoluble polymers and other solid supports are typically themore convenient form since they may be easily separated from liquids byfiltration. Such supports are routinely used in chemical and biochemicalsynthesis and include, for example, any insoluble inorganic or organicmaterial that is compatible with chemical and biological syntheses andassays such as glasses, silicates, cross-linked polymers such ascross-linked polystyrenes, polypropylenes, polyacrylamides,polyacrylates and sand, metals, and metal alloys. For example, theα-haloenamine reagent support may comprise poly(N,N-disubstitutedacrylamide), e.g., poly(N,N-dialkyl substituted acrylamide) or acopolymer thereof. Preferred materials include polystyrene-basedpolymers and copolymers. Commercially available materials includeTentaGel resin and ArgoGel (Bayer), bothpolystyrene/divinylbenzene-poly(ethylene glycol) graft copolymers (with˜1-2% cross-linking) and 1% cross-linked polystyrene/divinylbenzenecopolymer (ACROS) available in a range of particle sizes (e.g., 200-400mesh).

[0044] In general, solid supports may be in the form of beads,particles, sheets, dipsticks, rods, membranes, filters, fibers (e.g.,optical and glass), and the like or they may be continuous in design,such as a test tube or micro plate, 96 well or 384 well or higherdensity formats or other such micro plates and micro titer plates. Thus,for example, one, a plurality of, or each of the wells of a micro titerplate (96 well, 384 well or greater) or other multi well formatsubstratum may have the α-haloenamine reagent of the present inventiontethered to its surface. Alternatively, beads, particles or other solidsupports having an α-haloenamine reagent of the present invention boundto its surface may be added to one, a plurality of, or each of the wellsof a micro titer plate or other multi well substratum. Furthermore, ifthe solid support (whether in the form of a bead, particle, multi wellmicro titer plate, etc.) comprises poly(N,N-disubstituted acrylamide) oranother polymer having tertiary amides chemically accessible at itssurface, these tertiary amides may be converted to immobilizedα-haloenamines of the present invention using a pentavalent phosphoroushalide as otherwise described herein; stated another way, the source ofthe tertiary amide, from which the immobilized α-haloenamine of thepresent invention is derived may simply be a polymeric materialcomprising chemically accessible tertiary amides.

[0045] Solid-phase, polymer bound reagents, however, are not withouttheir shortcomings. For example, phase differences obtained byheterogeneous, insoluble supports can create diffusion limitations dueto the polymer matrix and this, in turn, can lead to reduced reactivityand selectivity as compared to classical, solution-phase synthesis.Furthermore, the insoluble nature of these supports can make synthesisand characterization of the polymer-reagent complex difficult.Accordingly, selectively soluble supports are preferred for someapplications.

[0046] In general, any polymeric material which is soluble under one setof conditions and insoluble under a second set of conditions may be usedas a selectively soluble support of the present invention provided thisgroup does not interfere with the synthesis of or react with any of thereaction products or intermediates. Exemplary soluble polymers includelinear polystyrene, polyethylene glycol, and their various polymers andcopolymers derivatized with tertiary amides which may then be convertedto α-haloenamines. In general, however, polyethylene glycol ispreferred. Polyethylene glycol exhibits solubility in a wide range oforganic solvents and water but is insoluble in hexane, diethyl ether,and tert-butyl methyl ether. Precipitation using these solvents orcooling of polymer solutions in ethanol or methanol yields crystallinepolyethylene glycol which can be purified by simple filtration.Attaching a haloenamine group to the polyethylene glycol thus allows forhomogeneous reaction conditions while permitting for relatively easypurification.

[0047] The α-haloenamine functionality or component of the α-haloenaminereagent is preferably attached to the support by means of a linker. Theonly requirement is that the linker be able to withstand the conditionsof the reaction in which the haloenamine reagent will be employed. Inone embodiment, the linker is selectively cleavable under a set ofconditions to permit cleavage of the enamine from the support. Inanother embodiment, the linker is not.

[0048] A great number of cleavable linkers have been developed over theyears to allow many multistep organic syntheses to be performed. Theselinkers have generally been classified into several major classes ofcleavage reaction (with some overlap between classes): (a)electrophilically cleaved linkers, (b) nucleophilically cleaved linkers,(c) photocleavable linkers, (d) metal-assisted cleavage procedures, (e)cleavage under reductive conditions, and (f) cycloaddition- andcycloreversion-based release. See, e.g., Guillier et al., Linkers andCleavage Strategies in Sold-Phase Organic Synthesis and CombinatorialChemistry, Chem. Rev. 2000, 100, 2091-2157.

[0049] More typically, the linker is non-cleavable and merelyconstitutes a chain of atoms connecting the α-haloenamine to the solidsupport. The only requirement is that the sequence not react with any ofthe final products or intermediates. Thus, for example, any of thestandard chemistries used to attach molecules to a solid support may beused to immobilize the α-haloenamine or, more preferably, a tertiaryamide precursor which is then converted to the α-haloenamine using apentavalent phosphorous halide. More specifically, a solid phaseα-chloroenamine reagent may be derived from a polystyrene supportedtertiary amide and PCl₅, with the polystyrene supported tertiary amide,in turn, being derived from polystyrene and a chloro-substitutedtertiary amide in the presence of FeCl₃ (see Example 2). Alternatively,styrene (or another polymerizable monomer) having a tertiary amide as asubstituent on the phenyl ring may be polymerized to form a polymerhaving a pendant tertiary amide which, as described elsewhere herein,may be converted to an α-haloenamine moiety using a pentavalentphosphorous halide, followed by treatment with a base.

[0050] Regardless of whether the linker is cleavable or non-cleavable,it may optionally include a spacer having a length and/or includedmoieties which provide the α-haloenamine reagent with more“solution-like” properties and better solvent compatibility. In general,the spacer group, if present, may be any atom, or linear, branched, orcyclic series of atoms which distance the α-haloenamine group from thesupport. The atoms, for example, may be selected from carbon, oxygen,nitrogen, sulfur and silicon. Preferred spacers include polyethyleneglycol and alkyl chains.

[0051] In one embodiment of the present invention, one of R₁ and R₄comprises a support and R₂, R₃ and the carbon atom to which they areattached are members of a carbocylic or heterocyclic ring:

[0052] wherein R₁, R₂, R₃, R₄ and X are as previously defined and R₅ isan atom or chain of atoms, which together with R₂ and R₃ define acarbocyclic or heterocyclic structure. If the structure is heterocyclo,the hetero atoms are preferably selected from oxygen and sulfur; basicnitrogens are preferably not included as a ring atom. In addition, theatom or chain of atoms comprising R₅ may be substituted with one or morehydrocarbyl, substituted hydrocarbyl, hetero atom(s) or heterocyclosubstituent. For example, together R₂, R₃, R₅ along with the carbon atomto which R₂ and R₃ are attached may comprise a cycloalkyl ring such ascyclopentyl or a five or six-membered heterocyclic ring. In anotherembodiment, R₃ comprises a support which enables physical separation ofthe reagent from a liquid composition, and any two of R₁, R₂, and R₄ andthe atoms to which they are attached are members of a heterocyclic ring:

[0053] wherein R₁, R₂, R₃, R₄, and X are as previously defined and R₅ isan atom or a chain of atoms, and R₆ is a bond, an atom or chain ofatoms, wherein R₅, together with R₁ and R₄, or R₆ together with R₁ andR₂, or R₂ and R₄ define a carbocyclic or heterocyclic structure. If thering is heterocyclo, the hetero atoms are preferably selected fromoxygen and sulfur; again, basic nitrogens are preferably not included asa ring atom. In each of these embodiments, R₅ preferably comprises twoor three chain atoms selected from carbon, oxygen and sulfur, and R₆ ispreferably a bond or an atom selected from carbon, oxygen and sulfur,thereby defining in each instance, a five or six membered heterocycle.In addition, the atom or chain of atoms or which R₅ and R₆ are comprisedmay optionally be substituted with one or more hydrocarbyl, substitutedhydrocarbyl, hetero atom(s) or heterocyclo substituents.

[0054] C. Haloenamine Reactions

[0055] The α-haloenamines of the present invention and, in particular,the immobilized α-haloenamines of the present invention may be used in avariety of syntheses to convert hydroxy-containing and thiol-containingcompounds to the corresponding halides. To avoid or at least minimizeunwanted side reactions, the hydroxy or thiol-containing compoundspreferably have an absence of other unprotected moieties which are alsoreactive with α-haloenamines. For example, basic primary and secondaryamine moieties will react with α-haloenamines and thus, it is preferredthat the hydroxy-containing or thiol-containing compound have an absenceof unprotected basic primary and secondary amine moieties when it isreacted with an α-haloenamine of the present invention. Suitableprotecting groups are identified, for example, in Protective Groups inOrganic Synthesis by T. W. Greene and P. G. M. Wuts, John Wiley andSons, 3rd ed. 1999.

[0056] In one embodiment, an immobilized α-haloenamine of the presentinvention is used to convert any of a wide range of carboxylic acids andthiocarboxylic acids to the corresponding acid halide. In a preferredembodiment, the carboxylic acids and thiocarboxylic acids have theformulae R^(ca)COOH and R^(ca)C(O)SH and the resulting correspondinghalides have the formulae R^(ca)COX wherein R^(ca) is hydrogen,hydrocarbyl, substituted hydrocarbyl, or heterocyclo and X is halogen.For many applications, it will be preferred that X be chlorine orbromine, typically chlorine. In addition, R^(ca) will often be alkyl,alkenyl, alkynyl, aryl, or heterocyclo optionally substituted with oneor more substituents that do not react with the COX functionality or thehaloenamine reagent, such as, one or more of halogen, heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl orheteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino,amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals,acetals, esters and ethers. For example, in one embodiment, X ischlorine or bromine, preferably chlorine, and R^(ca) is heterocyclo. Ingeneral, however, it is preferred that compositions containing twocarboxylic acid groups such as malonic acid be avoided since, uponreaction with an α-haloenamine, they may form a cyclic structure whichmay not be readily released.

[0057] In another embodiment, an immobilized α-haloenamine of thepresent invention is used to convert any of a wide range of alcohols tothe corresponding halides, provided the alcohol is not a substituent ofa carbocyclic, aromatic ring. In a preferred embodiment, the alcoholcorresponds to the formula (R^(a))₃COH wherein each R^(a) isindependently hydrogen, hydrocarbyl, substituted hydrocarbyl, orheterocyclo.

[0058] One particularly noteworthy class of alcohols which may beconverted to the corresponding halides by reaction with immobilizedα-haloenamines of the present invention are sugars. The conversion of asuitably protected sugar to the corresponding halide is depicted in thefollowing reaction scheme:

[0059] wherein

[0060] X is F, Cl, or Br;

[0061] each R″ is independently H, OZ, NHZ, SZ, or at least oneadditional saccharide unit;

[0062] R′=H, (CH₂)_(m)OZ, (CH₂)_(m)NHZ, or (CH₂)_(m)SZ, or at least oneadditional saccharide unit;

[0063] m=0-1;

[0064] n=1-2; and

[0065] Z is a protecting group.

[0066] Thus, for example, the immobilized α-haloenamine of the presentinvention may be used to convert the hemiacetal alcohol moiety of amonosaccharide, a disaccharide or a polysaccharide to a halide.Exemplary monosaccharides include allose, altrose, arabinose, erythrose,fructose, galactose, glucose, gulose, idose, lyxose, mannose, psicose,ribose, ribulose, sorbose, tagatose, talose, threose, xylose, xylulose,and erythrulose. Other exemplary sugars include the deoxy analogs, suchas deoxyribose, rhamnose and fucose.

[0067] In another embodiment, an immobilized α-haloenamine of thepresent invention is used to convert any of a wide range of silanols tothe corresponding silyl halides. In a preferred embodiment, the silanolcorresponds to the formula (R^(si))₃SiOH and the resulting silyl halidecorresponds to the formula (R^(si))₃SiX wherein each R^(si) isindependently hydrogen, hydrocarbyl, substituted hydrocarbyl,hydrocarbyloxy, substituted hydrocarbyloxy, or heterocyclo, and X ishalogen. For many applications, it will be preferred that X be chlorineor bromine, typically chlorine. In addition, R^(si) will often be alkyl,alkenyl, alkynyl or aryl, optionally substituted with one or moremoieties selected from halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protectedhydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol,sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers.

[0068] In another embodiment, an immobilized α-haloenamine of thepresent invention is used to convert any of a wide range of sulfonic orsulfinic acids to the corresponding sulfonyl or sulfinyl halide. In apreferred embodiment, the sulfonic or sulfinic acid corresponds to theformula R^(s)S(═O)_(n)OH, and the corresponding halide corresponds tothe formula R^(s)S(═O)_(n)X wherein R^(s) is hydrocarbyl, substitutedhydrocarbyl, or heterocyclo, X is halogen and n is 1 or 2. For manyapplications, it will be preferred that X be chlorine or bromine,typically chlorine. In addition, R^(s) will often be alkyl, alkenyl,alkynyl or aryl, optionally substituted with one or more moietiesselected from halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy,formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides,sulfoxides, sulfonamides, ketals, acetals, esters and ethers.

[0069] In another embodiment, an immobilized α-haloenamine of thepresent invention is used to convert any of a wide range of phosphinicacids, phosphonic acids or phosphates (or the thio analogs thereof) tothe corresponding phosphoryl halide. In a preferred embodiment, thephosphinic acid, phosphonic acid or phosphate corresponds to the formula(R^(P))_(u)P(O)(OH)_(3−u) and the corresponding halide corresponds tothe formula (R^(P))_(u)P(O)X_((3−u)) wherein each R^(P) is hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substitutedhydrocarbyloxy, or heterocyclo, X is halogen, and u is 0-2. In analternative embodiment, the phosphinc acid, phosphonic acid or phosphateis a thio analog corresponding to the formula (R^(P))_(u)P(O)(ZH)_(3−u)and the corresponding halide corresponds to the formula(R^(P))_(u)P(═O)X_((3−u)) wherein R^(P), X, and u are as previouslydefined and Z is O or S with at least one Z being S. For manyapplications, it will be preferred that X be chlorine or bromine,typically chlorine. In addition, R^(P) will often be alkyl, alkenyl,alkynyl or aryl, optionally substituted with one or more moietiesselected from halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy,formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides,sulfoxides, sulfonamides, ketals, acetals, esters and ethers. Ingeneral, however, it is preferred that phenylphosphinic acid (C₆H₅H₂PO₂)be avoided since, upon reaction with an α-haloenamine, it forms asubstance which is not readily released.

[0070] In another embodiment, an immobilized α-haloenamine of thepresent invention is used to dehydrate a non-aqueous solvent. Theprocess comprises combining the solvent with an immobilizedα-haloenamine reagent. The solvent may be any solvent which will notreact with α-haloenamines.

[0071] F. Definitions

[0072] The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include linear, branched or cyclicalkyl, alkenyl, alkynyl, and aryl moieties. These moieties also includealkyl, alkenyl, alkynyl, and aryl moieties substituted with otheraliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl andalkynaryl. Unless otherwise indicated, these moieties preferablycomprise 1 to 20 carbon atoms. In addition, the hydrocarbyl moieity maybe linked to more than one substitutable position of the tertiary amideor α-haloenamine of the present invention; for example, R₂ and R₃ of thetertiary amide or α-haloenamine may comprise the same chain of carbonatoms which, together with the carbon atoms to which R₂ and R₃ areattached define a carbocyclic ring.

[0073] The “substituted hydrocarbyl” moieties described herein arehydrocarbyl moieties which are substituted with at least one atom otherthan carbon, including moieties in which a carbon chain atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom. These substituentsinclude halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy,formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides,sulfoxides, sulfonamides, ketals, acetals, esters and ethers.

[0074] The term “heteroatom” shall mean atoms other than carbon andhydrogen.

[0075] Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

[0076] Unless otherwise indicated, the alkenyl groups described hereinare preferably lower alkenyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

[0077] Unless otherwise indicated, the alkynyl groups described hereinare preferably lower alkynyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

[0078] The terms “aryl” or “ar” as used herein alone or as part ofanother group denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

[0079] The terms “halogen” or “halo” as used herein alone or as part ofanother group refer to chlorine, bromine, fluorine, and iodine.

[0080] The terms “heterocyclo” or “heterocyclic” as used herein alone oras part of another group denote optionally substituted, fully saturatedor unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably onaryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy,amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides,ketals, acetals, esters and ethers. In addition, the heterocyclo moieitymay be linked to more than one substitutable position of the tertiaryamide or α-haloenamine of the present invention; for example, R. and R₂of the tertiary amide or α-haloenamine may comprise the same chain ofatoms which, together with the atoms to which R₁ and R₂ are attacheddefine a heterocyclo ring.

[0081] The term “heteroaromatic” as used herein alone or as part ofanother group denote optionally substituted aromatic groups having atleast one heteroatom in at least one ring, and preferably 5 or 6 atomsin each ring. The heteroaromatic group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl,oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.Exemplary substituents include one or more of the following groups:hydrocarbyl, substituted hydrocarbyl, halogen, heterocyclo, alkoxy,alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroarylrings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro,cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals,esters and ethers.

[0082] The term “hydrocarbyloxy,” as used herein denotes a hydrocarylgroup as defined herein bonded through an oxygen linkage (—O—), e.g.,RO— wherein R is hydrocarbyl.

[0083] “DBU” shall mean 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0084] “DBN” shall mean 1,5-diazabicyclo[4.3.0]non-5-ene.

[0085] The following examples will illustrate the invention.

EXAMPLE 1 Improved Synthesis ofN-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine

[0086]

[0087] Dimethylisobutyramide (25.00 g, 217.39 mmol) was added dropwiseover a 30-minute period to a solution of DMF (336 μL, 4.34 mmol) andPOCl₃ (60.70 mL, 651.22 mmol). The resulting solution was stirred atambient temperature and monitored by ¹H-NMR. After 3 hours the reactionwas concentrated under vacuum to remove all excess POCl₃. Triethylamine(33.30 mL, 238.91 mmol) was then added dropwise to a solution of theresulting chloroiminium salt dissolved in a small amount of CH₂Cl₂ (10mL). This mixture was distilled at 70 C. (100 Torr) to afford 22.70 g ofN-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine. ¹H NMR (CDCl₃): δ2.36 (s, 6H), 4.11 (s, 2H), 1.74 (br s, 6H).

EXAMPLE 2 Synthesis of N-(1-chloro-2-methylprop-1-enyl)-N-methylaminomethylpolystyrene

[0088]

[0089] N-Chloromethyl-N-methyl Isobutyramide

[0090] A mixture of N-methylisobutyramide (200.00 g, 1980 mmol) andparaformaldehyde (50.50 g, 1680 mmol) in chlorotrimethylsilane (860.40g, 7920 mmol) was slowly heated to reflux. At about 62 C., the reactionexothermed and most of the paraformaldehyde dissolved. This mixture wasrefluxed for an additional 4 hours, and then was filtered to removesolids. This was concentrated to remove nearly all the excess TMSCI, andthen again filtered to afford 219 g ofN-chloromethyl-N-methylisobutyramide. ¹H NMR (CDCl₃): (2 rotamers): δ5.33 (s) and 5.30 (s) [2H combined], 3.11 (s) and 2.97 (s) [3Hcombined], 2.93 (heptet, J=6.2 Hz) and 2.75 (heptet, J=6.4 Hz) [1Hcombined], 1.14 (d, J=6.2 Hz) and 1.10 (d, J=6.2 Hz) [6H combined].

[0091] N-Methyl Isobutyramidomethylpolystyrene

[0092] Anhydrous FeCl₃ (202.70 g, 1250 mmol) was added in portions to amechanically stirred mixture of 1% crosslinked styrene-divinylbenzenecopolymer (100 g, 960 mEq) and N-chloromethyl-N-methylisobutyramide(186.80 g, 1250 mmol) in CH₂Cl₂ (1L), maintaining the internal reactiontemperature between −5° C. to 5° C. The resulting yellow slurry wasstirred at room temperature for 5 days, and then was filtered and washedwith CH₂Cl₂ (3×), 1:1 aqueous 1N HCl/1,4-dioxane (1×), and then withportions of MeOH until the color was gone. The 1:1 1 N HCl/1,4-dioxanewash step was very exothermic and controlled by It adding the1,4-dioxane to the resin, and then cooling this stirred slurry with adry ice/acetone bath while 1N HCl was added slowly. Vacuum drying atroom temperature overnight afforded 193.0 g of the resin as an off-whitesolid. Amide loading on the resin was calculated to be 4.56 mmol/gmbased on elemental analysis. Magic Angle ¹³C NMR (CD₂Cl₂): (2 rotamers):δ 177.38 and 176.95 (CO), 53.12 and 50.57 (CH₂N), 34.70 and 34.00(NCH₃), 30.56 and 30.45 (CHMe₂), 20.03 and 19.53 (CH(CH₃)₂). FT-IR:1642.92 cm-1 (broad CO stretch). Anal. Calcd for 1.00 C₁₄H₁₉NO+0.10H₂O:C, 76.74; H, 8.83; N, 6.39; O, 8.03. Found: C, 76.65; H, 8.74; N, 6.30;O, 7.81.

[0093] N-(1-Chloro-2-methylprop-1-enyl)-N-methyl Aminomethylpolystyrene

[0094] N-methyl isobutyramidomethylpolystyrene (100.00 g, 456 mEq) waswashed twice with dry CH₃CN (@1.5L). A fresh portion of CH₃CN (1.5L) wasthen added, and the reaction was cooled with an ice-water bath whilePCl, (330.16 g, 1585 mmol) was added in portions, at a rate whichmaintained the internal reaction temperature from 10° C. to 17° C. Theresulting mixture was slowly stirred at room temperature for 4 hours,and then was filtered and washed with 2 portions of CH₃CN. The swelledpolymer was compacted 3-fold by washing with 3 portions of CHCl₃ ThisCH₃CN/CHCl₃ cycle of washes was repeated to completely remove the excessPCl₅.

[0095] A slurry of this chloroiminium chloride of N-methylisobutyramidomethylpolystyrene was prepared in anhydrous CHCl₃ (1.5 L).This was cooled with dry-ice/acetone to −10° C. while Et₃N (317 mL, 2275mmol) was added dropwise. A precipitate of Et₃NHCl did not form. Theresulting mixture was stirred at 0° C. for 2 hours, and then wasfiltered and washed sequentially with equal portions of CHCl₃, 1:2CH₃CN/CHCl₃, 1:1 CH₃CN/CHCl₃, and then CHCl₃. Reaction solvents wereanhydrous and the CHCl₃was stabilized with amylenes. Vacuum dryingafforded golden yellow N-(1-chloro-2-methylprop-1-enyl)-N-methylaminomethylpolystyrene.

[0096] Resin loading was determined by adding excess acetic acid (26.9mg) to a slurry of N-(1-chloro-2-methylprop-1-enyl)-N-methylaminomethylpolystyrene (96 mg) in CDCl₃ (800 mL), and integrating theacetyl peaks in the 1H NMR spectrum after 10 minutes of stirring at roomtemperature. A value of 2.64 mEq/gm was calculated from [(CH₃COClintegral)/(CH₃COOH integral)]×26.9 mg/60.05/0.096 g.

EXAMPLE 3 Synthesis of 1-methyl-4-(BOC amino)pyrrole-2-carbonyl Chloride

[0097]

[0098] N-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine (31 μL, 0.23mmol) was added to a mixture of 1-methyl-4-(BOCamino)pyrrole-2-carboxylic acid (50 mg, 0.21 mmol) in CDCl₃ (200 mL).After a few minutes, the ¹H-NMR of the reaction mixture showed completeconversion of the acid to the acid chloride. The proton spectrum of thissolution of acid chloride did not change on standing overnight at roomtemperature. ¹H NMR (CDCl₃): δ 7.35 (br s, 1H), 6.93 (d, J=2 Hz, 1H),6.46 (br s, 1H), 3.82 (s, 3H), 1.50 (s, 9H).

EXAMPLE 4 Synthesis of 1-methyl-4-(BOC amino)imidazole-2-carbonylChloride

[0099]

[0100] N-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine (660 μL, 4.99mmol) was added to a mixture of 1-methyl-4-(BOCamino)imidazole-2-carboxylic acid (1.00 g, 4.17 mmol) in CHCl₃ (8.00mL). After a few minutes, the ¹H-NMR of the reaction mixture showedcomplete conversion of the acid to the acid chloride. ¹H NMR (CDCl₃): δ7.48 (br s, 1H), 3.95 (s, 3H), 1.50 (s, 9H).

EXAMPLE 5 General Synthesis of Acid Chlorides UsingN-(1-chloro-2-methylprop-1-enyl)-N-methyl Aminomethylpolystyrene

[0101]

[0102] In a dry box, 2 equivalents ofN-(1-chloro-2-methylprop-1-enyl)-N-methyl aminomethylpolystyrene wasadded to a stirred 0.20M-0.25M mixture of ˜0.5-1.0 mmol of a carboxylicacid in CD₃CN. The resulting reaction mixture was monitored tocompletion by ¹H-NMR. Aliquots of the liquid phase containing the acidchloride were then derivatized by addition to small volumes of methanol,ethanol, or aqueous 40% MeNH₂. These reactions were monitored tocompletion over 1-3 h by ¹H-NMR and HPLC to form the ester or amide, andthen were concentrated under vacuum and characterized. Reverse phaseHPLC was carried out on an Agilent 1100 system using a Vydac 4.6×250 mmProtein & Peptide C18 column eluted at 1.2 mL/min with a linear gradientof 20% MeCN: 80% H₂O to 100% MeCN over a 15 minute period. Both solventscontained 0.1% TFA. The compounds of examples A-M were prepared by theseprocedures.

EXAMPLE 5A

[0103]

[0104] 2-Chloro-6-trimethylsilanyl benzoyl chloride was cleanly andcompletely formed from 2-chloro-6-trimethylsilanyl benzoic acid within 1h. ¹H NMR (CD₃CN): δ 7.30-7.13 (m, 3H), 0.00 (s, 9H). ¹³C NMR (CD₃CN): δ169.82 (CO), 142.34, 138.69, 133.82, 131.78, 130.75, 128.46, −1.04(SiCH₃).

[0105] Methyl 2-chloro-6-trimethylsilanyl benzoate formed cleanly andcompletely from the reaction of 2-chloro-6trimethylsilanyl benzoylchloride with methanol, to afford a single 254 nm HPLC peak at 12.604min. ¹H NMR (CD₃CN): δ 7.32-7.13 (m, 3H), 3.63 (s, 3H), 0.00 (s, 9H).¹³C NMR (CD₃CN): δ 168.70 (CO), 140.35, 138.45, 133.31, 130.60, 130.22,52.22 (OCH₃), −1.44 (SiCH₃). GC-MS showed a single peak in the TIC: m/z227 (M⁺−Me).

[0106] N-Methyl-2-chloro-6-trimethylsilanyl benzamide formed cleanly andcompletely from the reaction of 2-chloro-6-trimethylsilanyl benzoylchloride with aqueous 40% methylamine, to afford a single 254 nm HPLCpeak at 8.417 mi. ¹H NMR (CD₃CN): δ 7.28-7.06 (m, 3H), 2.58 (d, J=4.83Hz, 3H), 0.00 (s, 9H). ¹³C NMR (CD₃CN): δ 140.38, 133.27, 129.97,129.66, 25.45 (NCH₃), −1.11(SiCH₃) Calculated C₁₁H₁₇CINOSi (M⁺+1) exactmass=242.0762. Found 242.0749.

EXAMPLE 5B

[0107]

[0108] 2-Hydroxy benzoyl chloride was cleanly and completely formed from2-hydroxy benzoic acid within 15 min. ¹H NMR (CD₃CN): δ 9.37 (s, 1H),8.11 (dd, J =8.2 Hz, 1.7 Hz, 1H), 7.67 (d of t, J=7.8 Hz, 1.7 Hz, 1H),7.11-7.04 (m, 2H). ¹³C NMR (CD₃CN): δ 172.42 (CO), 161.19, 138.76,134.20, 120.75, 118.08.

[0109] Methyl 2-hydroxy benzoate was formed cleanly and completely fromthe reaction of 2-hydroxy benzoyl chloride with methanol, to afford asingle 254 nm HPLC peak at 8.510 min. ¹H NMR (CD₃CN): δ 10.66 (br s,1H), 7.82 (dd, J=8.0 Hz, 1.7 Hz, 1H), 7.48 (d of t, J=7.8 Hz, 1.7 Hz,1H), 6.94-6.89 (m, 2H), 3.89 (s, 3H). ¹³C NMR (CD₃CN): δ 170.70 (CO),161.49, 136.04, 130.11, 119.58, 117.45, 112.71, 52.34 (OCH₃). GC-MSshowed a single peak in the TIC: m/z 152 (M⁺).

EXAMPLE5C

[0110]

[0111] 4-Hydroxy benzoyl chloride was cleanly and completely formed from4-hydroxy benzoic acid within 15 min. ¹H NMR (CD₃CN): δ 8.31 (br s, 1H),8.02 (d, J=8.9 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H). ¹³C NMR (CD₃CN): δ164.18, 134.50, 116.13.

[0112] Methyl 4-hydroxy benzoate formed cleanly and completely from thereaction of 4-hydroxy benzoyl chloride with methanol, to afford a single254 nm HPLC peak at 5.237 min. ¹H NMR (CD₃CN): δ 7.88 (d, J=8.8 Hz, 2H),6.88 (d, J=8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR (CD₃CN): δ 166.65, 161.45,131.69, 115.33, 51.49 (OCH₃).

[0113] N-Methyl 4-hydroxy benzamide formed cleanly and completely fromthe reaction of 4-hydroxy benzoyl chloride with aqueous 40% methylamine,to afford a broad 254 nm HPLC peak at 2.512 min. ¹H NMR (CD₃CN): δ 7.66(d, J=8.8 Hz, 2H), 7.51 (br s, 1H), 6.85 (d, J=8.6 Hz, 2H), 2.83 (d,J=4.7 Hz, 3H). ¹³C NMR (CD₃CN): δ 128.97, 115.07, 25.76 (NCH₃).Calculated C₈H₁₀NO₂ (M⁺+1) exact mass=152.0706. Found 152.0602.

EXAMPLE5D

[0114]

[0115] 2-Nitrobenzoyl chloride was cleanly and completely formed from2-nitrobenzoic acid within 20 min. ¹H NMR (CD₃CN): δ 8.13 (d, J=2.4 Hz,1H), 7.91-7.81 (m, 3H). ¹³C NMR (CD₃CN): δ 134.71, 133.89, 129.10,125.00.

[0116] Methyl 2-nitrobenzoate formed cleanly and completely from thereaction of 2-nitrobenzoyl chloride with methanol, to afford a single304 nm HPLC peak at 7.284 min. ¹H NMR (CD₃CN): δ 7.94-7.92 (m, 2H),7.79-7.69 (m, 3H), 3.87 (s, 3H). ¹³C NMR (CD₃CN): δ 165.89, 133.56,132.62, 130.04, 127.18, 124.21, 53.05 (OCH₃).

[0117] N-Methyl-2-nitrobenzamide formed cleanly and completely from thereaction of 2-nitrobenzoyl chloride with aqueous 40% methylamine, toafford a broad 304 nm HPLC peak at 3.153 min. ¹H NMR (CD₃CN): δ 7.96 (d,J=8.0 Hz, 1H), 7.74-78.53 (m, 3H), 6.94 (br s, 1H), 2.84 (d, J=4.8 Hz,3H). ¹³C NMR (CD₃CN): δ 166.63, 133.70, 130.83, 128.95, 124.42, 25.97(NCH₃). Calculated C₈H₉N₂O₃ (M⁺+1) exact mass=181.0608. Found 181.0621.

EXAMPLE 5E

[0118]

[0119] (5-Chlorocarbonyl-1-methyl-1H-pyrrol-3-yl)-carbamic acidtert-butyl ester was cleanly and completely formed from4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carboxylic acidovernight. ¹H NMR (CD₃CN): δ 7.35 (br s, 1H), 7.03 (d, J=1.9 Hz, 1H),3.79 (s, 3H), 1.47 (s, 9H). ¹³C NMR (CD₃CN): δ 156.20, 125.54, 114.59,36.96, 27.69.

[0120] Methyl4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carboxylate formedcleanly and completely from the reaction of(5-chlorocarbonyl-1-methyl-1H-pyrrol-3-yl)-carbamic acid tert-butylester with methanol, to afford a single 304 nm HPLC peak at 8.547 min.¹H NMR (CD₃CN): δ 7.27 (br s, 1H), 7.03 (br s, 1H), 6.63 (s, 1H), 3.82(s, 3H), 3.74 (s, 3H), 1.46 (s, 9H). ¹³C NMR (CD₃CN): δ 161.35, 153.37,123.07, 119.54, 107.68, 50.70 (OCH₃), 36.13, 27.73. CalculatedC₁₂H₁₉N₂O₄ (M⁺+1) exact mass=255.1339. Found 255.1333.

[0121] (1-Methyl-5-methylcarbamoyl-1H-pyrrol-3-yl)-carbamic acidtert-butyl ester formed cleanly and completely from the reaction of(5-chlorocarbonyl-1-methyl-1H-pyrrol-3-yl)-carbamic acid tert-butylester with aqueous 40% methylamine, to afford a single 304 nm HPLC peakat 5.870 min. ¹H NMR (CD₃CN): δ 7.27, (br s, 1H), 6.82 (br s, 1H), 6.58(br s, 1H), 6.45 (s, 1H), 3.81 (s, 3H), 2.76 (d, J=4.7 Hz, 3H), 1.46 (s,9H). ¹³C NMR (CD₃CN): δ 162.25, 153.43, 122.49, 122.34, 102.76, 35.78,35.75, 27.76, 25.09 (NCH₃). Calculated C₁₂H₂₀N₃O₃ (M⁺+1) exactmass=254.1499. Found 254.1504.

EXAMPLE 5F

[0122]

[0123] (2-Chlorocarbonyl- 1-methyl-1H-imidazol-4-yl)-carbamic acidtert-butyl ester cleanly and completely formed from4-tert-butoxycarbonylamino-1-methyl-1H-imidazole-2-carboxylic acidwithin 1 hour. ¹H NMR (CD₃CN): δ 8.02 (br s, 1H), 7.50 (br s, 1H), 3.89(s, 3H), 1.48 (s, 9H).

[0124] Methyl4-tert-butoxycarbonylamino-1-methyl-1H-imidazole-2-carboxylate formedcleanly and completely from the reaction of(2-chlorocarbonyl-1-methyl-1H-imidazol-4-yl)-carbamic acid tert-butylester with methanol, to afford a single 304 nm HPLC peak at 6.088 min.¹H NMR (CD₃CN): δ 9.11 (br s, 1H), 7.35 (br s, 1H), 3.98 (s, 3H), 3.92(s, 3H), 1.49 (s, 9H). Calculated C₁₁H₁₈N₃O₄ (M⁺+) exact mass=256.1292.Found 256.1291.

[0125] (1-Methyl-2-methylcarbamoyl-1H-imidazol-4-yl)-carbamic acidtert-butyl ester formed cleanly and completely from the reaction of(2-chlorocarbonyl-1-methyl-1H-imidazol-4-yl)-carbamic acid tert-butylester with aqueous 40% methylamine, to afford a single 304 nm HPLC peakat 5.642 min. ¹H NMR (CD₃CN): δ 7.36, (br s, 1H), 7.04 (br s, 1H), 3.94(s, 3H), 2.81 (s, 3H), 1.47 (s, 9H). Calculated C₁₁H₁₉N₄O₃ (M⁺⁺1) exactmass=255.1452. Found 255.1429.

EXAMPLE 5G

[0126]

[0127] 1H-Pyrrole-2-carbonyl chloride cleanly and completely formed from1H-pyrrole-2-carboxylic acid within 15 min. ¹H NMR (CD₃CN): δ 7.26 (brm, 1H), 7.21 (br m, 1H), 6.37 (br m, 1H). ¹³C NMR (CD₃CN): δ 129.13,122.80, 112.04.

[0128] Methyl 1H-pyrrole-2-carboxylate formed cleanly and completelyfrom the reaction of 1H-pyrrole-2-carbonyl chloride with methanol, toafford a single 254 nm HPLC peak at 4.763 min. ¹H NMR (CD₃CN): δ 9.98(br m, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 6.23 (m, 1H), 3.79 (s, 3H). ¹³CNMR (CD₃CN): δ 123.48, 115.00, 109.96, 50.96 (OCH₃). GC-MS showed asingle peak in the TIC: m/z 125 (M⁺).

[0129] N-Methyl-1H-pyrrole-2-carboxamide formed cleanly and completelyfrom the reaction of 1H-pyrrole-2-carbonyl chloride with aqueous 40%methylamine, to afford a single 254 nm HPLC peak at 2.789 min. ¹H NMR(CD₃CN): δ 9.89, (br s, 1H), 6.88 (m, 1H), 6.67 (br s, 1H), 6.59 (m,1H), 6.17 (m, 1H), 2.81 (d, J=4.8 Hz, 3H). ¹³C NMR (CD₃CN): δ 121.17,109.24, 108.97, 25.11 (NCH₃). Calculated C₆H₉N₂O (M⁺+1) exactmass=125.0709. Found 125.0717.

EXAMPLE 5H

[0130]

[0131] Furan-2-carbonyl chloride cleanly and completely formed fromfuran-2-carboxylic acid within 25 min. ¹H NMR (CD₃CN): δ 7.93 (dd, J=1.0Hz, 1.7 Hz, 1H), 7.63 (dd, J=0.7 Hz, 3.7 Hz, 1H), 6.74 (dd, J=1.7 Hz,3.7 Hz, 1H). ¹³C NMR (CD₃CN): δ 151.39, 145.92, 125.82, 113.83.

[0132] Methyl furan-2-carboxylate formed cleanly and completely from thereaction of furan-2-carbonyl chloride with methanol, to afford a single254 nm HPLC peak at 4.987 min. ¹H NMR (CD₃CN): δ 7.70 (dd, J=0.8 Hz, 1.7Hz, 1H), 7.20 (dd, J=0.8 Hz, 3.4 Hz, 1H), 6.59 (dd, J=1.8 Hz, 3.4 Hz,1H), 3.83 (s, 3H). ¹³C NMR (CD₃CN): δ 159.04, 147.14, 144.78, 118.01,112.13, 51.60 (OCH₃). GC-MS showed a single peak in the TIC: m/z 126(M⁺).

[0133] N-Methyl furan-2-carboxamide formed cleanly and completely fromthe reaction of furan-2-carbonyl chloride with aqueous 40% methylamine,to afford a single 254 nm HPLC peak at 2.662 min. ¹H NMR (CD₃CN): δ7.56, (dd, J=0.8 Hz, 1.7 Hz, 1H), 6.98 (dd, J=0.8 Hz, 3.4 Hz, 1H), 6.54(dd, J=1.8 Hz, 3.5 Hz, 1H),2.83 (d, J=4.8 Hz, 3H). ¹³C NMR (CD₃CN): δ144.59, 113.00, 111.90, 25.05 (NCH₃). Calculated C₆H₈NO₂ (M⁺+1) exactmass=126.0550. Found 126.0553.

EXAMPLE 5I

[0134]

[0135] (1-Chlorocarbonyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethylester cleanly and completely formed from2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid within 20 min. ¹HNMR (CD₃CN): o 7.85 (d, J=7.5 Hz, 2H), 7.68 (d, J=7.1 Hz, 2H), 7.44 (t,J=7.3 Hz, 2H), 7.35 (t, J=7.4 Hz, 2H), 6.44 (br s, 1H), 4.48-4.23 (m,4H), 1.48 (d, J=7.0 Hz, 3H). ¹³C NMR (CD₃CN): δ 176.13, 156.08, 144.16,141.38, 127.95, 127.33, 125.35, 120.21, 66.84, 59.27, 47.15, 15.75.

[0136] Methyl 2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionate formedcleanly and completely from the reaction of(1-chlorocarbonyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester withmethanol, to afford a single 254 nm HPLC peak at 10.353 min. ¹H NMR(CD₃CN): δ 7.84 (d, J=7.6 Hz, 2H), 7.68 (d, J=6.8 Hz, 2H), 7.43 (t,J=7.3Hz, 2H), 7.35 (t, J=7.4 Hz, 2H), 6.07 (br s, 1H), 4.39-4.15 (m, 4H),3.67 (s, 3H), 1.35 (d, J=7.3 Hz, 3H). ¹³C NMR (CD₃CN): δ 173.65, 156.07,144.34, 141.35, 127.91, 127.32, 125.38, 120.19, 66.46, 51.98 (OCH₃),49.86, 47.21, 17.05. Calculated C₁₉H₂₀NO₄ (M⁺+1) exact mass=326.1387.Found 326.1398.

EXAMPLE 5J

[0137]

[0138] Trichloroacetyl chloride cleanly and completely formed fromtrichloroacetic acid within 20 min. ¹³C NMR (CD₃CN): δ 164.09, 93.87.GC-MS showed a single peak in the TIC with a spectrum that was identicalto authentic material: m/z 145 (M⁺−Cl).

[0139] Methyl trichloroacetate formed cleanly and completely from thereaction of trichloroacetyl chloride with methanol. ¹³C NMR (CD₃CN): δ162.55, 89.75, 56.14 (OCH₃). GC-MS showed a single peak in the TIC: m/z141 (M⁺−Cl).

[0140] N-Methyl trichloroacetamide formed cleanly and completely fromthe reaction of trichloroacetyl chloride with aqueous 40% methylamine.¹³C NMR (CD₃CN): δ 162.50, 92.74, 27.41 (NCH₃). GC-MS showed a singlepeak in the TIC: mlz 175 (M⁺). Calculated C₃H₈Cl₃N₂O (M+NH₄ ⁺) exactmasses for chlorine isotopes=192.9697, 194.9667, 196.9638. Found192.9732, 194.9711, 196.9643.

EXAMPLE 5K

[0141]

[0142] Trimethylacetyl chloride cleanly and completely formed fromtrimethylacetic acid within 2 hours. ¹H NMR (CD₃CN): δ 1.33 (s, 9H). ¹³CNMR (CD₃CN): δ 180.62, 49.50, 26.38.

[0143] Ethyl trimethylacetate formed cleanly and completely from thereaction of trimethylacetyl chloride with ethanol. ¹H NMR (CD₃CN): δ4.04 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H), 1.12 (s, 9H). GC-MSshowed a single peak in the TIC: m/z 130 (M⁺).

[0144] N-Methyl trimethylacetamide formed cleanly and completely fromthe reaction of trimethylacetyl chloride with aqueous 40% methylamine.¹H NMR (CD₃CN): δ 6.29 (br s, 1H), 2.65 (d, J=4.7 Hz, 3H), 1.12 (s, 9H).¹³C NMR (CD₃CN): δ 27.00, 25.65 (NCH₃).

EXAMPLE 5L

[0145]

[0146] But-2-enoyl chloride cleanly and completely formed frombut-2-enoic acid within 20 min, and was identical to authenic compound.¹H NMR (CD₃CN): δ 7.32 (d of q, J=6.9 Hz, 15.1 Hz, 1H), 6.19 (d of q,J=1.6 Hz, 15.1 Hz, 1H), 1.98 (dd, J=1.6 Hz, 6.9 Hz, 3H). ¹³C NMR(CD₃CN): δ 154.78, 127.12, 17.77.

EXAMPLE 5M

[0147]

[0148] Priopionyl chloride cleanly and completely formed from priopionicacid within 15 min. ¹H NMR (CD₃CN): δ 3.00 (q, J=7.3 Hz, 2H), 1.16 (t,J=7.2 Hz, 3H). ¹³C NMR (CD₃CN): δ 175.10, 40.87, 8.97.

EXAMPLE 6 General Synthesis of Chlorides from Alcohols UsingN-(1-chloro-2-methylprop-1-enyl)-N-methyl Aminomethylpolystyrene

[0149]

[0150] In a dry box, 2 equivalents (per OH group) ofN-(1-chloro-2-methylprop-1-enyl)-N-methyl aminomethylpolystyrene wasadded to a stirred mixture of ˜0.5-1.0 mmol of an alcohol in CD₃CN (3mL). The resulting reaction mixture was monitored and characterized by¹H-NMR, ¹³C-NMR, and MS. The following compounds of examples N-R wereprepared by these procedures.

EXAMPLE 6N

[0151]

[0152] n-Butyl chloride cleanly and completely formed from n-butanolwithin 15 min. ¹H NMR (CD₃CN): δ 3.60 (t, J=6.7 Hz, 2H), 1.75 (pentet,J=7.0 Hz, 2H), 1.45 (hextet, J=7.4 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H). ¹³CNMR (CD₃CN): δ 45.11, 34.56, 19.89, 12.74.

EXAMPLE 6O

[0153]

[0154] An 8.8 to 1 mixture of cyclopentyl chloride to cyclopenteneformed from cyclopentanol within 15 min. Data for cyclopentyl chloride:¹H NMR (CD₃CN): δ 4.41 (m, 1H), 2.06-1.93 (m, 2H), 1.88-1.74 (m, 4H),1.68-1.55 (m, 2H). ¹³C NMR (CD₃CN): δ 62.63, 36.90, 22.81.

EXAMPLE 6P

[0155]

[0156] A single anomer of1-chloro-2,3,4,6-tetra-O-benzyl-D-glucopyranose was cleanly andcompletely formed from 2,3,4,6-tetra-O-benzyl-D-glucopyranose within 3hours. ¹H NMR (CD₃CN): δ 7.36-7.16 (m, 20H), 6.32 (d, J=3.6 Hz, 1H),4.87-4.43 (m, 8H), 4.01-3.95 (m,1H), 3.89-3.83 (m,1H), 3.73-3.66 (m,2H), 3.64-3.55 (m, 2H). ¹³C NMR (CD₃CN): δ 139.03, 138.64, 138.49,138.18, 128.60, 128.56, 128.48, 128.46, 128.27, 128.15, 128.12, 128.09,128.07, 127.85, 127.84, 127.74, 94.31, 81.10, 80.00, 76.75, 75.28,74.94, 73.87, 73.04, 72.39, 68.45.

EXAMPLE 6Q

[0157]

[0158] A 1.9 to 1 mixture of 3-chloro-1-butene to 1-chloro-2-buteneformed from 3-hydroxy-1-butene within 15 min. Data for3-chloro-1-butene: ¹H NMR (CD₃CN): δ 6.06-5.93 (m, 1H), 5.29 (d, J=16.9Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 4.63-4.53 (m, 1H),1.57 (d, J=6.6 Hz,3H). ¹³C NMR (CD₃CN): δ 140.24, 115.25, 58.35, 24.35. Data for1-chloro-2-butene: ¹H NMR (CD₃CN): δ 5.91-5.60 (m, 2H), 4.08 (d, J=7.0Hz, 2H), 1.72 (d, J=6.2 Hz, 3H). ¹³C NMR (CD₃CN): δ 31.07, 127.47,45.54, 16.94.

EXAMPLE 6R

[0159]

[0160] 3-Chloro-1-butyne was cleanly and completely formed from3-hydroxy-1-butyne within 20 min. ¹H NMR (CD₃CN): δ 4.73 (dd, J=2.3 Hz,6.8 Hz, 1H), 2.88 (d, J=2.4 Hz, 1H), 1.68 (d, J=6.8 Hz, 3H). ¹³C NMR(CD₃CN): δ 83.20, 74.24, 43.73, 25.98.

EXAMPLE 7 General Synthesis of Silyl Chlorides, Phosphinyl Chlorides,and Sulfonyl Chlorides Using N-(1-chloro-2-methylprop-1-enyl)-N-methylAminomethylpolystyrene

[0161]

[0162] In a dry box, 2 equivalents (per OH group) ofN-(1-chloro-2-methylprop-1-enyl)-N-methyl aminomethylpolystyrene wasadded to a stirred mixture of ˜0.5 mmol of an SiOH, PO₂H, PO₃H₂ or SO₃Hcontaining compound in CD₃CN (3 mL). The resulting reaction mixture wasmonitored to completion by ¹H-NMR. Aliquots of the liquid phasecontaining the corresponding SiCl, POCl, POCl₂ or SO₂Cl compound werethen derivatized by addition to small volumes of methanol or aqueous 40%MeNH₂. These reactions were monitored to completion over 1-3 h by ¹H-NMRand HPLC to form the ester or amide, and then were concentrated undervacuum and characterized. Reverse phase HPLC was carried out on anAgilent 1100 system using a Vydac 4.6×250 mm Protein & Peptide C18column eluted at 1.2 mL/min with a linear gradient of 20% MeCN: 80% H₂Oto 100% MeCN over a 15 minute period. Both solvents contained 0.1% TFA.The compounds of examples S-W were prepared by these procedures.

EXAMPLE 7S

[0163]

[0164] tert-Butyidimethylsilyl chloride was cleanly and completelyformed from tert-butyidimethylsilanol in 20 min. ¹H NMR (CD₃CN): δ 0.95(s, 9H), 0.35 (s, 6H). ¹³C NMR (CD₃CN): δ 24.78, 18.86, −2.19.

[0165] Methyl ether formed cleanly. ¹H NMR (CD₃CN): δ 3.38 (s, 3H), 0.83(s, 9H), 0.00 (s, 6H). ¹³C NMR (CD₃CN): δ 50.48 (OCH₃), 25.37, 18.08,−6.57.

EXAMPLE 7T

[0166]

[0167] Triphenylsilanol was cleanly converted to triphenylsilyl chloridein 20 min. ¹³C NMR (CD₃CN): δ 135.10, 132.67, 131.26, 128.55.

[0168] Methyl ether formed cleanly. ¹H NMR (CD₃CN): δ 7.55-7.50 (m, 6H),7.41-7.29 (m, 9H), 3.31 (s, 3H). ¹³C NMR (CD₃CN): δ 135.15, 133.97,130.01, 127.77, 48.66 (OCH₃). GC-MS showed a single peak in the TIC: m/z290 (M⁺).

EXAMPLE7U

[0169]

[0170] Phosphoric acid diphenyl ester was cleanly and completelyconverted to phosphorochloridic acid diphenyl ester over 3 hours. ³¹PNMR (CD₃CN): δ −24.06.

[0171] Phosphoric acid methyl ester diphenyl ester formed cleanly andcompletely from the reaction of phosphorochloridic acid diphenyl esterwith methanol, to afford a single 254 nm HPLC peak at 5.036 min. ¹H NMR(CD₃CN): δ 7.43-7.33 (m, 4H), 7.28-7.18 (m, 6H), 3.94 (d, J=11.5 Hz,3H). ³¹P NMR (CD₃CN): δ −9.53. Calculated C₁₃H₁₄O₄P (M⁺+1) exactmass=265.0624. Found 265.0619.

EXAMPLE 7V

[0172]

[0173] Phenylphosphoryl dichloride was cleanly and completely formedfrom phenylphosphonic acid over 8 hours. ³¹P NMR (CD₃CN): δ 36.56. ¹³CNMR (CD₃CN): δ 135.25 (d, J=3.8 Hz), 134.36 (d, J=153.4 Hz), 130.36 (d,J=13.9 Hz), 129.68 (d, J=18.3 Hz).

[0174] Phenylphosphonic acid dimethyl ester formed cleanly and andcompletely from the reaction of phenylphosphoryl dichloride withmethanol to afford a single 254 nm HPLC peak at 4.932 min. ¹H NMR(CD₃CN): δ 7.81-7.49 (m, 5H), 3.70 (d, J=11.1 Hz, 6H). ³¹P NMR (CD₃CN):δ 21.73. Calculated C₈H₁₂O₃P (M⁺+1) exact mass=187.0519. Found 187.0492.

[0175] Phenylphosphonic acid bis(N-methylamide) formed cleanly andcompletely from the reaction of phenylphosphoryl dichloride with gaseousmethylamine. ¹H NMR (CD₃CN): δ 7.73-7.65 (m, 2H), 7.46-7.35 (m, 3H),2.40 (d, J=11.9 Hz, 6H). ³¹P NMR (CD₃CN): δ 23.60. ¹³C NMR (CD₃CN): δ131.54 (d, J=9.3 Hz), 130.96 (br), 128.26 (d, J=12.9 Hz), 25.80.Calculated C₈H₁₄N₂O₂P (M⁺+1) exact mass=185.0838. Found 185.0838.

EXAMPLE 7W

[0176]

[0177] p-Toluene sulfonyl chloride was cleanly and completely formedfrom p-toluene sulfonic acid monohydrate over 1 hour. ¹H NMR (CD₃CN): δ7.97 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 2.49 (s, 3H). ¹³C NMR(CD₃CN): δ 148.12, 130.78, 127.13, 21.07.

[0178] p-Toluene sulfonamide formed cleanly from the reaction ofp-toluene sulfonyl chloride with aqueous 40% methylamine to afford asingle 254 nm HPLC peak at 6.089 min. ¹H NMR (CD₃CN): δ 7.74 (d, J=8.2Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 3.67 (s, 3H), 2.41 (s, 3H). CalculatedC₈H₁₂NO₂S (M⁺+1) exact mass=186.0583. Found 186.0610.

EXAMPLE 8 Synthesis of N-tert-butyl Benzamide UsingN-(1-chloro-2-methylprop-1-enyl)-N-methyl Aminomethylpolystyrene

[0179]

[0180] A mixture of benzoic acid (1.00 g, 8.2 mmol) andN-(1-chloro-2-methylprop-1-enyl)-N-methyl aminomethylpolystyrene (1.55mequiv/g, 8.00 g, 12.4 mequiv) in anhydrous acetonitrile (25 mL) wasstirred at ambient temperature with no significant exotherm. Benzoylchloride was cleanly formed over 10 minutes. ¹H NMR (CD₃CN): δ 8.17-8.12(m, 2H), 7.83-7.76 (m, 1H), 7.64-7.57 (m, 2H). GC-MS m/z 140 (M⁺).

[0181] The reaction mixture was then filtered under a nitrogenatmosphere and the resin washed with 25 mL of dry acetonitrile. Thecombined acetonitrile filtrates containing the benzoyl chloride wereadded to a solution of tert-butylamine (2.58 mL, 24.6 mmol) in CH₂Cl₂(20 mL). After 10 minutes the reaction was diluted with CH₂Cl₂ andwashed with dilute aqueous HCl, followed with dilute aqueous NaOH. TheCH₂C₂ solution was dried (MgSO₄) and concentrated to afford an 82% yield(1.19 g) of tert-butyl benzamide as a white solid. ¹H NMR (CD₃CN): δ7.74-7.68 (m, 2H), 7.50-7.36 (m, 3H), 5.93 (br s, 1H), 1.47 (s, 9H).GC-MS m/z 177 (M⁺).

EXAMPLE 9 Synthesis of4-[(4-tert-butoxycarbonylamino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1-methyl-1H-imidazole-2-CarboxylicAcid Methyl Ester Using N-(1-chloro-2-methylprop-1-enyl)-N-methylAminomethylpolystyrene

[0182]

[0183] A mixture of4-tert-butoxycarbonylamino-1-methyl-1H-imidazole-2-carboxylic acid (1.30g, 5.40 mmol) and N-(1-chloro-2-methylprop-1-enyl)-N-methylaminomethylpolystyrene (1.55 mequiv/g, 6.96 g, 10.77 mequiv) inanhydrous acetonitrile (20 mL) was stirred at ambient temperature. Over15 minutes, all of the BOCNH-Im-COOH dissolved and was converted to thecorresponding acid chloride.

[0184] The reaction mixture was then filtered under a nitrogenatmosphere and the resin washed with 20 mL of dry acetonitrile. Theacetonitrile filtrates containing the acid chloride were combined andadded dropwise to a vigorously stirred 2-phase mixture of a solution of4-amino-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (643 mg,4.15 mmol) in CH₂Cl₂ (20 mL) and a solution of Na₂CO₃ (572 mg, 5.40mmol) in H₂O (20 mL). The resulting reaction mixture was stirred for 5minutes, and then was diluted with CH₂Cl₂ and H₂O. The CH₂Cl₂ solutionwas isolated, dried (MgSO₄), and concentrated to afford a quantitativeyield (1.64 g) of4-[(4-tert-butoxycarbonylamino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1-methyl-1H-imidazole-2-carboxylicacid methyl ester as a very pure off-white solid. Reverse phase HPLC ofthis material was carried out on an Agilent 1100 system using a Vydac4.6×250 mm Protein & Peptide C18 column eluted at 1.2 mL/min with alinear gradient of 20% MeCN: 80% H₂O to 40% MeCN: 60% H₂O over a 15minute period. Both solvents contained 0.1% TFA. A single 304 nm HPLCpeak eluted at 12.223 minutes. ¹H NMR (CD₃CN): δ 7.56 (s, 1H), 7.14 (brs, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.90 (s, 3H), 1.51 (s, 9H).

EXAMPLE 10 Synthesis of1-methyl-4-{[1-methyl-4-({1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonyl}-amino)-1H-imidazole-2-carbonyl]-amino}-1H-pyrrole-2-carboxylicAcid Methyl Ester Using N-(1-chloro-2-methylprop-1-enyl)-N-methylAminomethylpolystyrene

[0185]

[0186] Trimethylsilyl triflate (150 μL, 0.81 mmol) was added in a singleportion to a mixture of1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carboxylicacid (200 mg, 0.80 mmol) in anhydrous acetonitrile (8.00 mL). Thesolution which formed within a few moments was transferred to solidN-(1-chloro-2-methyl prop-1-enyl)-N-methyl aminomethylpolystyrene (1.55mequiv/g, 1.04 g, 1.61 mequiv). After stirring at ambient temperaturefor 10 minutes, an equal volume of anhydrous CHCl₃ (stabilized withamylenes) was added and the mixture was filtered in an inert atmosphere.The resin was washed with an additional 10 mL of anhydrous CHCl₃(stabilized with amylenes), and the combined filtrates containing the1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonylchloride were added dropwise to a vigorously stirred 2-phase mixture ofa solution of4-[(4-amino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1-methyl-1H-pyrrole-2-carboxylicacid methyl ester (171 mg, 0.62 mmol) in CHCl₃ (10 mL), and a solutionof Na₂CO₃ (170 mg, 1.60 mmol) in H₂O (5 mL). The resulting reactionmixture was stirred for 5 minutes, and then was diluted with CHCl₃ andH2O. The CHCl₃ solution was isolated, dried (MgSO₄), and concentrated toafford a 59% yield (240 mg) of1-methyl-4-{[1-methyl-4-({1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonyl}-amino)-1H-imidazole-2-carbonyl]-amino}-1H-pyrrole-2-carboxylicacid methyl ester as a very pure off-white solid. Reverse phase HPLC ofthis material was carried out on an Agilent 1100 system using a Vydac4.6×250 mm Protein & Peptide C18 column eluted at 1.2 mL/min with alinear gradient of 20% MeCN: 80% H₂O to 40% MeCN 60% H₂O over a 15minute period. Both solvents contained 0.1% TFA. A single 304 nm HPLCpeak eluted at 10.847 minutes. ¹H NMR (CD₃CN plus TFA): δ 10.90 (s, 1H),10.71 (s, 1H), 9.49 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.65 (m, 2H),7.46 (d, J=1.8 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 4.15 (s, 3H), 4.12 (s,3H), 4.11 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H).

What is claimed is:
 1. A process for the preparation of anα-haloenamine, the process comprising combining a tertiary amide with apentavalent phosphorous halide in a solvent to form an α-haloiminiumsalt and converting the α-haloiminium salt to the α-haloenamine with abase, the pentavalent phosphorous halide having at least two halogenatoms bonded to the pentavalent phosphorous atom.
 2. The process ofclaim 1 wherein the base is a tertiary amine.
 3. The process of claim 1wherein the base is triethylamine.
 4. The process of claim 1 wherein theα-haloenamine is an α-chloroenamine, α-bromoenamine, α-fluoroenamine orα-iodoenamine.
 5. The process of claim 1 wherein the pentavalentphosphorous halide is phosphorous pentachloride or phosphorouspentabromide.
 6. The process of claim 1 wherein the pentavalentphosphorous halide is phosphorous pentachloride.
 7. The process of claim1 wherein the α-haloenamine is α-chloroenamine, α-bromoenamine, orα-iodoenamine and the process comprises combining a tertiary amide withphosphorous pentachloride or phosphorous pentabromide.
 8. The process ofclaim 1 wherein the process comprises combining a tertiary amide withphosphorous pentachloride to form α-chloroenamine and displacing thechloride of the α-chloroenamine with bromide, fluoride or iodide.
 9. Theprocess of claim 1 wherein the solvent comprises acetonitrile.
 10. Theprocess of any one of claims 1 to 9 wherein the tertiary amide iscovalently linked to a support which enables physical separation of theα-haloenamine from a liquid composition.
 11. The process of claim 10wherein the tertiary amide is covalently linked to an inorganic supportwhich enables physical separation of the α-haloenamine from a liquidcomposition, the inorganic support being selected from the groupconsisting of silicates, quartz and aluminium.
 12. The process of claim10 wherein the tertiary amide is covalently linked to a polymericsupport which enables physical separation of the α-haloenamine from aliquid composition.
 13. The process of any one of claims 1 to 9 whereinthe tertiary amide is a tertiary amide reagent having the formula:

wherein R₁ and R₄ are independently hydrocarbyl, substitutedhydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy; and R₂ andR₃ are independently hydrogen, hydrocarbyl, substituted hydrocarbyl,hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl,substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substitutedhydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl,halo, cyano, or nitro, provided at least one of R₁, R₂, R₃ and R₄comprises a support which enables physical separation of the tertiaryamide from a liquid mixture.
 14. The process of claim 13 wherein threeof R₁, R₂, R₃ and R₄ are alkyl.
 15. The process of claim 13 wherein twoof R₁, R₂, R₃ and R₄ in combination define a carbocyclic or heterocycloring.
 16. The process of claim 13 wherein three of R₁, R₂, R₃ and R₄ arealkyl and the other is covalently linked to a polymeric support
 17. Theprocess of claim 13 wherein the tertiary amide reagent ispoly(N,N-disubstituted acrylamide).
 18. The process of claim 13 whereinthe tertiary amide reagent is a polymer having N,N-disubstituted amidemoieties.
 19. The process of claim 13 wherein the tertiary amide reagentis a polymer having N,N-dialkyl substituted amide moieties.
 20. Theprocess of claim 13 wherein the amide moiety of the tertiary amidereagent is covalently attached to the phenyl ring of a polystyrenepolymer or copolymer through one of R¹, R², R³ or R⁴.
 21. A process fordehydrating a non-aqueous solvent, the process comprising combining thesolvent with an immobilized α-haloenamine reagent.
 22. The process ofclaim 21 wherein the α-haloenamine is α-chloroenamine.
 23. The processof claim 21 wherein the α-haloenamine is covalently linked to apolymeric support.
 24. The process of claim 21 wherein the α-haloenamineis covalently linked to a polymeric support, the α-haloenamine beingderived from an N,N-disubstituted amide moiety of the polymeric support.25. A process for converting a hydroxy-containing compound or athiol-containing compound to the corresponding halide, the processcomprising contacting the hydroxy-containing compound orthiol-containing compound with an immobilized α-haloenamine.
 26. Theprocess of claim 25 wherein the compound is a hydroxy-containingcompound.
 27. The process of claim 25 wherein the compound is ahydroxy-containing compound selected from the group consisting ofalcohols, carboxylic acids, silanols, sulfonic acids, sulfinic acids,phosphinic acids, phosphoric acids, and phosphates.
 28. The process ofclaim 25 wherein the compound is a thiol-containing compound.
 29. Theprocess of claim 25 wherein the compound is a thiol-containing compoundselected from the group consisting of thiocarboxylic acids,thiophosphonic acids, and thiophosphoric acids.
 30. The process of anyone of claims 25 to 29 wherein the immobilized α-haloenamine is animmobilized α-chloroenamine.
 31. The process of claim 30 wherein theα-chloroenamine is covalently linked to an inorganic support.
 32. Theprocess of claim 30 wherein the α-chloroenamine is covalently linked toa polymeric support.
 33. The process of any one of claims 25 to 29wherein the immobilized α-haloenamine is an immobilized α-bromonamine.34. The process of claim 33 wherein the α-bromonamine is covalentlylinked to a polymeric support.
 35. The process of claim 33 wherein theα-bromonamine is covalently linked to an inorganic support.
 36. Theprocess of any one of claims 25 to 29 wherein the immobilizedα-haloenamine is an immobilized α-fluoroenamine.
 37. The process ofclaim 36 wherein the α-fluoroenamine is covalently linked to aninorganic support.
 38. The process of claim 36 wherein theα-fluoroenamine is covalently linked to a polymeric support.
 39. Theprocess of any one of claims 25 to 29 wherein the immobilizedα-haloenamine is an immobilized α-iodoenamine.
 40. The process of claim39 wherein the α-iodoenamine is covalently linked to a polymericsupport.
 41. The process of claim 39 wherein the α-iodoenamine iscovalently linked to an inorganic support.
 42. An immobilizedα-haloenamine reagent having the formula:

wherein R₁ and R₄ are independently hydrocarbyl, substitutedhydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy; R₂ and R₃are independently hydrogen, hydrocarbyl, substituted hydrocarbyl,hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl,substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substitutedhydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl,halo, cyano, or nitro, and X is halo, provided at least one of R₁, R₂,R₃ and R₄ comprises a support which enables physical separation of thereagent from a liquid mixture.
 43. The immobilized α-haloenamine ofclaim 42 wherein one of R₁, R₂, R₃ and R₄ comprises a support selectedfrom the group consisting of inorganic and polymeric supports.
 44. Theimmobilized α-haloenamine of claim 42 wherein one of R₁, R₂R₃ and R₄comprises an inorganic support selected from the group consisting ofsilicates, quartz and aluminium.
 45. The immobilized α-haloenamine ofclaim 42 wherein at least one of R₁, R₂, R₃ and R₄ comprises a polymericsupport.
 46. The immobilized α-haloenamine of claim 42 wherein two ofR₁, R₂R₃ and R₄, together with the atoms to which they are attached,define a carbocyclic or heterocyclo ring.
 47. The immobilizedα-haloenamine of claim 42 wherein one of R₁, R₂, R₃ and R₄ comprises apolymeric support which, under a first set of conditions is soluble inthe liquid mixture and, under a second set of conditions is insoluble inthe liquid mixture.
 48. The immobilized α-haloenamine of claim 42wherein at least one of R₁, R₂, R₃ and R₄ comprises a polyethyleneglycol support which, under a first set of conditions is soluble in theliquid mixture and, under a second set of conditions is insoluble in theliquid mixture.
 49. The immobilized α-haloenamine of claim 42 wherein atleast one of R₁, R₂, R₃ and R₄ comprises a support which enablesphysical separation of the reagent from a liquid mixture, and the othersof R₁, R₂, R₃ and R₄ are hydrocarbyl.
 50. The immobilized α-haloenamineof claim 42 wherein at least one of R₁, R₂, R₃ and R₄ comprises asupport which enables physical separation of the reagent from a liquidmixture, and the others of R₁, R₂, R₃ and R₄ are substitutedhydrocarbyl.
 51. The immobilized α-haloenamine of claim 42 wherein atleast one of R₁, R₂, R₃ and R₄ comprises a support which enablesphysical separation of the reagent from a liquid mixture, the others ofR₁, R₂, R₃ and R₄ are substituted hydrocarbyl, and the hydrocarbylsubstituent(s) are selected from the group consisting of halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol,sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers.52. The immobilized α-haloenamine of claim 42 wherein at least one ofR₁, R₂, R₃ and R₄ comprises a support which enables physical separationof the reagent from a liquid mixture and the others of R₁, R₂, R₃ andR₄are alkyl.
 53. The immobilized α-haloenamine of claim 42 wherein atleast one of R₁ and R₄ comprises a support which enables physicalseparation of the reagent from a liquid mixture, and R₂, R₃ and thecarbon atom to which they are attached are members of a carbocylic orheterocyclic ring.
 54. The immobilized α-haloenamine of claim 42 whereinR₃ comprises a support which enables physical separation of the reagentfrom a liquid mixture, and any two of R₁, R₂, and R₄ and the atoms towhich they are attached are members of a heterocyclic ring.
 55. Theimmobilized α-haloenamine of claim 42 wherein R₂ comprises a supportwhich enables physical separation of the reagent from a liquid mixture,and R₁ and R₄ and the atoms to which they are attached are members of aheterocyclic ring.
 56. The immobilized α-haloenamine of claim 42 whereinthe immobilized haloenamine is N-(1-chloro-2-methylprop-1-enyl)-N-methylaminomethylpolystyrene.
 57. The immobilized α-haloenamine of claim 42wherein the support is 1% cross linked polystyrene/divinyl benzenecopolymer.
 58. The immobilized α-haloenamine of claim 42 wherein thesupport comprises the surface of a well of a substratum.
 59. Theimmobilized α-haloenamine of claim 42 wherein the support comprises thesurface of a well of a multi-well substratum.
 60. The immobilizedα-haloenamine of claim 42 wherein the support comprises the surface of awell of a micro titer plate comprising at least 96 wells.
 61. Theimmobilized α-haloenamine of claim 42 wherein the α-haloenamine isimmobilized on the surface of a polymer and the α-haloenamine comprisesthe reaction product of a tertiary amide moiety covalently linked to thepolymer.
 62. The immobilized α-haloenamine of claim 42 wherein theα-haloenamine is immobilized on the surface of a polymer and theα-haloenamine comprises the reaction product of a N,N-dialkylsubstituted tertiary amide moiety covalently attached to the surface ofthe polymer.
 63. The immobilized α-haloenamine of claim 42 wherein theα-haloenamine is immobilized on the surface of a polymer or copolymer ofstyrene and the α-haloenamine comprises the reaction product of atertiary amide moiety covalently attached to the surface of the polymer.64. The immobilized α-haloenamine of claim 42 wherein the α-haloenamineis immobilized on the surface of a poly(N,N-disubstituted acrylamide)polymer or copolymer.